tbuckley/cabot-search huggingface dataset:
Intermediate acoustic-to-semantic representations link behavioral and neural responses to natural sounds
Authors: Bruno L. Giordano, Michele Esposito, Giancarlo Valente, Elia Formisano
Journal: Nature Neuroscience (2023)

Recognizing sounds implicates the cerebral transformation of input waveforms into semantic representations. Although past research identified the superior temporal gyrus (STG) as a crucial cortical region, the computational fingerprint of these cerebral transformations remains poorly characterized. Here, we exploit a model comparison framework and contrasted the ability of acoustic, semantic (continuous and categorical) and sound-to-event deep neural network representation models to predict perceived sound dissimilarity and 7 T human auditory cortex functional magnetic resonance imaging responses. We confirm that spectrotemporal modulations predict early auditory cortex (Heschl's gyrus) responses, and that auditory dimensions (for example, loudness, periodicity) predict STG responses and perceived dissimilarity. Sound-to-event deep neural networks predict Heschl's gyrus responses similar to acoustic models but, notably, they outperform all competing models at predicting both STG responses and perceived dissimilarity. Our findings indicate that STG entails intermediate acoustic-to-semantic sound representations that neither acoustic nor semantic models can account for. These representations are compositional in nature and relevant to behavior.
Light-stimulated insulin secretion from pancreatic islet-like organoids derived from human pluripotent stem cells
Authors: Jieun Choi, Eunji Shin, Jinsu Lee, Somayadineshraj Devarasou, Dongkyu Kim, Jennifer H. Shin, Jin-Ho Choi, Won Do Heo, Yong-Mahn Han
Journal: Molecular Therapy (2023)
Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy
Authors: Kelly Hanna, Julio Nieves, Christine Dowd, Kristina Oresic Bender, Pallavi Sharma, Baljit Singh, Mark Renz, James N. Ver Hoeve, Diana Cepeda, Claire M. Gelfman, Brigit E. Riley, Ruslan N. Grishanin
Journal: Molecular Therapy (2023)

Blue cone monochromacy (BCM) is a rare X-linked retinal disease characterized by the absence of L- and M-opsin in cone photoreceptors, considered a potential gene therapy candidate. However, most experimental ocular gene therapies utilize subretinal vector injection which would pose a risk to the fragile central retinal structure of BCM patients. Here we describe the use of ADVM-062, a vector optimized for cone-specific expression of human L-opsin and administered using a single intravitreal (IVT) injection. Pharmacological activity of ADVM-062 was established in gerbils, whose cone-rich retina naturally lacks L-opsin. A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli. To identify potential first-in-human doses we evaluated ADVM-062 in non-human primates. Cone-specific expression of ADVM-062 in primates was confirmed using ADVM-062.myc, a vector engineered with the same regulatory elements as ADVM-062. Enumeration of human OPN1LW.myc-positive cones demonstrated that doses ≥3 × 10
Aqueous Two‐Phase Emulsion Bioresin for Facile One‐Step 3D Microgel‐Based Bioprinting
Authors: Qingbo Wang, Özge Karadas, Oskar Backman, Luyao Wang, Tuomas Näreoja, Jessica M. Rosenholm, Chunlin Xu, Xiaoju Wang
Journal: Advanced Healthcare Materials (2023)

Abstract Microgel assembly as void‐forming bioinks in 3D bioprinting has evidenced recent success with a highlighted scaffolding performance of these bottom‐up biomaterial systems in supporting the viability and function of the laden cells. Here, a ternary‐component aqueous emulsion is established as a one‐step strategy to integrate the methacrylated gelatin (GelMA) microgel fabrication and assembly through vat photopolymerization in situ using digital light processing (DLP)‐based bioprinting. The as‐proposed aqueous emulsion is featured with the partitioning of a secondary photo‐crosslinkable polysaccharide, methacrylated galactoglucomannan (GGMMA) derived from plant source in both the dispersed phase of GelMA droplets and the continuous phase of dextran (Dex). As an emulgator, GGMMA renders enhanced stability of the aqueous emulsion bioresins. Strategically, the photo‐crosslinkable GGMMA adheres the GelMA microgels that are conveniently converted from emulsion droplets to form hydrogel construct in layer‐by‐layer curing to accommodate the laden cells directly mixed in the aqueous emulsion. The spatially interconnected void space left by the removal of Dex benefits the cell growth under the guidance of the microgel surface and supports cell colonization within the macroscopic porous hydrogel. This work amends a low‐concentration and cost‐effective bioresin that is highly applicable for facilely fabricating microgel assembly as a porous hydrogel construct in DLP‐based bioprinting.
Pharmaceutical treatment of bone loss: From animal models and drug development to future treatment strategies
Authors: Mikkel Bo Brent
Journal: Pharmacology & Therapeutics (2023)

Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.
Efficacy and moderators of short-term psychodynamic psychotherapy for depression: A systematic review and meta-analysis of individual participant data
Authors: Frederik J. Wienicke, Manfred E. Beutel, Rüdiger Zwerenz, Elmar Brähler, Peter Fonagy, Patrick Luyten, Matthew Constantinou, Jacques P. Barber, Kevin S. McCarthy, Nili Solomonov, Peter J. Cooper, Leonardo De Pascalis, Robert Johansson, Gerhard Andersson, Alessandra Lemma, Joel M. Town, Allan A. Abbass, Bita Ajilchi, Mary Beth Connolly Gibbons, Jaime López-Rodríguez, Valerio Villamil-Salcedo, Giuseppe Maina, Gianluca Rosso, Jos W.R. Twisk, William J. Burk, Jan Spijker, Pim Cuijpers, Ellen Driessen
Journal: Clinical Psychology Review (2023)

Short-term psychodynamic psychotherapy (STPP) is frequently used to treat depression, but it is unclear which patients might benefit specifically. Individual participant data (IPD) meta-analyses can provide more precise effect estimates than conventional meta-analyses and identify patient-level moderators. This IPD meta-analysis examined the efficacy and moderators of STPP for depression compared to control conditions.PubMed, PsycInfo, Embase, and Cochrane Library were searched September 1st, 2022, to identify randomized trials comparing STPP to control conditions for adults with depression. IPD were requested and analyzed using mixed-effects models.IPD were obtained from 11 of the 13 (84.6%) studies identified (n = 771/837, 92.1%; mean age = 40.8, SD = 13.3; 79.3% female). STPP resulted in significantly lower depressive symptom levels than control conditions at post-treatment (d = -0.62, 95%CI [-0.76, -0.47], p < .001). At post-treatment, STPP was more efficacious for participants with longer rather than shorter current depressive episode durations.These results support the evidence base of STPP for depression and indicate episode duration as an effect modifier. This moderator finding, however, is observational and requires prospective validation in future large-scale trials.
Nutritional Modulation of Associations between Prenatal Exposure to Persistent Organic Pollutants and Childhood Obesity: A Prospective Cohort Study
Authors: German Cano-Sancho, Charline Warembourg, Nuria Güil, Nikos Stratakis, Aitana Lertxundi, Amaia Irizar, Sabrina Llop, Maria-Jose Lopez-Espinosa, Xavier Basagaña, Juan Ramon González, Xavier Coumoul, Sílvia Fernández-Barrés, Jean-Philippe Antignac, Martine Vrijheid, Maribel Casas
Journal: Environmental Health Perspectives (2023)

Background: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disorders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations. Objectives: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on childhood obesity. Methods: We used data from to the Spanish INfancia y Medio Ambiente–Environment and Childhood (INMA) birth cohort, on POPs and nutritional biomarkers measured in maternal blood collected at the first trimester of pregnancy and child anthropometric measurements at 7 years of age. Six organochlorine compounds (OCs) [dichlorodiphenyldichloroethylene, hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH) and polychlorinated biphenyls 138, 153, 180] and four per- and polyfluoroalkyl substances (PFAS) were measured. Nutrients included vitamins (D, B12, and folate), polyunsaturated fatty acids (PUFAs), and dietary carotenoids. Two POPs–nutrients mixtures data sets were established: a) OCs, PFAS, vitamins, and carotenoids (n=660), and b) OCs, PUFAs, and vitamins (n=558). Joint associations of mixtures on obesity were characterized using Bayesian kernel machine regression (BKMR). Relative importance of biomarkers and two-way interactions were identified using gradient boosting machine, hierarchical group lasso regularization, and BKMR. Interactions were further characterized using multivariate regression models in the multiplicative and additive scale. Results: Forty percent of children had overweight or obesity. We observed a positive overall joint association of both POPs–nutrients mixtures on overweight/obesity risk, with HCB and vitamin B12 the biomarkers contributing the most. Recurrent interactions were found between HCB and vitamin B12 across screening models. Relative risk for a natural log increase of HCB was 1.31 (95% CI: 1.11, 1.54, pInteraction=0.02) in the tertile 2 of vitamin B12 and in the additive scale a relative excess risk due to interaction of 0.11 (95% CI: 0.02, 0.20) was found. Interaction between perfluorooctane sulfonate and β-cryptoxanthin suggested a protective effect of the antioxidant on overweight/obesity risk. Conclusion: These results support that maternal nutritional status may modulate the effect of prenatal exposure to POPs on childhood overweight/obesity. These findings may help to develop a biological hypothesis for future toxicological studies and to better interpret inconsistent findings in epidemiological studies. https://doi.org/10.1289/EHP11258
Psychiatric Morbidity in Women With Previous Gestational Diabetes Mellitus: A Nationwide Register-Based Cohort Study
Authors: Maria Hornstrup Christensen, Marianne Skovsager Andersen, Katrine Hass Rubin, Ellen Aagaard Nohr, Jori Aalders, Christina Anne Vinter, Dorte Moeller Jensen
Journal: Diabetes Care (2023)

OBJECTIVE To investigate associations between previous gestational diabetes mellitus (GDM) and incident psychiatric morbidity, and to explore the role of subsequent diabetes development in psychiatric morbidity risk. RESEARCH DESIGN AND METHODS A nationwide register-based cohort study including all women delivering in Denmark from 1997 to 2018 was conducted. GDM exposure was based on diagnosis code, whereas psychiatric morbidity outcome was based on diagnosis code and psychopharmacological medication use. Multiple Cox regression and mediation analyses were performed. RESULTS In a study population of 660,017 women, previous GDM was associated with increased risk of depression based on diagnosis code and/or medication use (adjusted hazard ratio [aHR] 1.22 [95% CI 1.18–1.27]), any psychiatric diagnosis (aHR 1.20 [95% CI 1.13–1.27]), and any psychopharmacological medication use (aHR 1.21 [95% CI 1.17–1.25]). Moreover, risk of depressive and anxiety disorders, as well as antidepressant and antipsychotic medication use, was increased, with aHRs ranging from 1.14 (95% CI 1.05–1.25) to 1.32 (95% CI 1.22–1.42). No associations were found regarding substance use disorders, psychotic disorders, bipolar disorders, postpartum psychiatric disease, or anxiolytic medication use. Psychiatric morbidity risk was higher in women with versus without subsequent diabetes development. However, GDM history affected risk estimates only in women without subsequent diabetes. Subsequent diabetes mediated 35–42% of the associations between GDM and psychiatric morbidity. CONCLUSIONS GDM was associated with increased psychiatric morbidity risk. Subsequent diabetes development played a significant role in future psychiatric morbidity risk after GDM, although it only partly explained the association.
Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma
Authors: Hesam Movassagh, Mary Prunicki, Abhinav Kaushik, Xiaoying Zhou, Diane Dunham, Eric M. Smith, Ziyuan He, German R. Aleman Muench, Minyi Shi, Annika K. Weimer, Shu Cao, Sandra Andorf, Amir Feizi, Michael P. Snyder, Pejman Soroosh, Elizabeth D. Mellins, Kari C. Nadeau
Journal: Allergy (2023)

Abstract Background The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma, are not well understood. We investigated whether ambient levels of fine PM with aerodynamic diameter ≤2.5 microns (PM 2.5 ) are associated with alterations in circulating monocytes in children with or without asthma. Methods Monocyte phenotyping was performed by cytometry time‐of‐flight (CyTOF). Cytokines were measured using cytometric bead array and Luminex assay. ChIP‐Seq was utilized to address histone modifications in monocytes. Results Increased exposure to ambient PM 2.5 was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by the upregulation of proinflammatory mediators, such as TNF, IL‐6, and IL‐8, upon stimulation with house dust mite or lipopolysaccharide. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes. Conclusion The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution‐induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.
Disease-specific mortality and major adverse cardiovascular events after bariatric surgery: a meta-analysis of age, sex, and BMI-matched cohort studies
Authors: Beibei Cui, Guohui Wang, Pengzhou Li, Weizheng Li, Zhi Song, Xulong Sun, Liyong Zhu, Shaihong Zhu
Journal: International Journal of Surgery (2023)

Background: Obesity is associated with a significant predisposition towards cardiovascular events and acts as an important risk factor for mortality. Herein, we conducted a comprehensive meta-analysis to estimate the protective effect of bariatric surgery on disease-specific mortality and major adverse cardiovascular events (MACEs) in patients with severe obesity. Methods: PubMed and Embase were searched from inception to 4 June 2022. Eligible studies were age, sex, and BMI-matched cohort studies. The protocol for this meta-analysis was registered on PROSPERO (ID: CRD42022337319). Results: Forty matched cohort studies were identified. Bariatric surgery was associated with a lower risk of disease-specific mortality including cancer mortality [hazard ratio with 95% confidence interval: 0.46 (0.37–0.58)], cardiovascular mortality [0.38 (0.29–0.50)], and diabetes mortality [0.25 (0.11–0.57)]. Bariatric surgery was associated with a lower incidence of MACEs [0.58 (0.51–0.66)] and its components including all-cause mortality [0.52 (0.47–0.58)], atrial fibrillation [0.79 (0.68–0.92)], heart failure [0.52 (0.42–0.65)], myocardial infarction [0.55 (0.41–0.74)], and stroke [0.75 (0.63–0.89)]. According to subgroup analysis on all-cause mortality, patients with severe obesity and type 2 diabetes benefited more from bariatric surgery than those with severe obesity only (heterogeneity between groups: P =0.001), while different surgical approaches brought similar benefits (heterogeneity between groups: P =0.87). Conclusions: This meta-analysis of 40 matched cohort studies supports that bariatric surgery reduces disease-specific mortality and incidence of both MACEs and its components in patients with severe obesity compared with nonsurgical subjects. Bariatric surgery deserves a more aggressive consideration in the management of severe obesity.
Pharmacogenomics: Driving Personalized Medicine
Authors: Wolfgang Sadee, Danxin Wang, Katherine Hartmann, Amanda Ewart Toland
Journal: Pharmacological Reviews (2023)

<h3>Abstract</h3> Personalized medicine tailors therapies, disease prevention, and health maintenance to the individual, with pharmacogenomics serving as a key tool to improve outcomes and prevent adverse effects. Advances in genomics have transformed pharmacogenetics, traditionally focused on single gene-drug pairs, into pharmacogenomics, encompassing all "-omics" fields (e.g., proteomics, transcriptomics, metabolomics, and metagenomics). This review summarizes basic genomics principles relevant to translation into therapies, assessing pharmacogenomics' central role in converging diverse elements of personalized medicine. We discuss genetic variations in pharmacogenes (drug-metabolizing enzymes, drug transporters, and receptors), their clinical relevance as biomarkers, and the legacy of decades of research in pharmacogenetics. All types of therapies, including proteins, nucleic acids, viruses, cells, genes, and irradiation, can benefit from genomics, expanding the role of pharmacogenomics across medicine. Food and Drug Administration approvals of personalized therapeutics involving biomarkers increase rapidly, demonstrating the growing impact of pharmacogenomics. A beacon for all therapeutic approaches, molecularly targeted cancer therapies highlight trends in drug discovery and clinical applications. To account for human complexity, multicomponent biomarker panels encompassing genetic, personal, and environmental factors can guide diagnosis and therapies, increasingly involving artificial intelligence to cope with extreme data complexities. However, clinical application encounters substantial hurdles, such as unknown validity across ethnic groups, underlying bias in health care, and real-world validation. This review address the underlying science and technologies germane to pharmacogenomics and personalized medicine, integrated with economic, ethical, and regulatory issues, providing insights into the current status and future direction of health care. <h3>Significance Statement</h3> Personalized medicine aims to optimize health care for the individual patients with use of predictive biomarkers to improve outcomes and prevent adverse effects. Pharmacogenomics drives biomarker discovery and guides the development of targeted therapeutics. This review addresses basic principles and current trends in pharmacogenomics, with large-scale data repositories accelerating medical advances. The impact of pharmacogenomics is discussed, along with hurdles impeding broad clinical implementation, in the context of clinical care, ethics, economics, and regulatory affairs.
Aurora A kinase inhibition elevates PD-L1 expression and compromises its anti-tumor efficacy
Authors: Xiaobo Wang, Jing Huang, Fenglin Liu, Qian Yu, Ruina Wang, Jiaqi Wang, Zewen Zhu, Juan Yu, Jun Hou, Joong Sup Shim, Wei Jiang, Zengxia Li, Yuanyuan Zhang, Yongjun Dang
Journal: Journal of Clinical Investigation (2023)

Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated PD-L1 expression in a panel of tumor cells both in vitro and in vivo. The upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cGAS, suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS-STING-NF-κB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced antitumor effects of alisertib in immune-competent mice. Our results revealed the immunomodulatory functions of Aurora A inhibitors,which provide a plausible explanation for the poor clinical outcomes of Aurora A inhibitors in clinical settings and suggest a potential approach to improve their anti-tumor efficacy.
Vaxman I, Gertz MA. How I approach smoldering multiple myeloma. <i>Blood</i>. 2022;140(8):828-838.
Journal: Blood (2023)

phrase "time of venetoclax" should read "time off venetoclax" in the sentence "In an update from the MURANO study, among 18 response-evaluable patients with a median time of venetoclax of 24 months, the ORR to retreatment was 72%, with 50% of patients remaining on therapy after a median of 11 months."